To avoid the treatment's deadly effect, cancer cells aggressively activate their own DNA breaks

Genotoxic Cancer Therapy (GCT) kills cancer cells by causing extensive DNA damage. Among them, Radiation therapy (RT) is the most widely used genotoxic cancer therapy. When radiation passes through cells, the energy it carries triggers extensive DNA damage, including double strand breaks (DSBs), single strand breaks (SSBs), and interstrand crosslinks (ICSLs) of DNA, which trigger cell death or cell cycle arrest.

In clinical treatment, however, some cancer cells survive radiotherapy, resulting in cancer recurrence following treatment. The resistance of cancer cells to radiotherapy is a significant impediment to successful cancer progression control, and we still don't understand fully the processes by which cancer cells attenuate radiotherapy's deadly effect.

Cancer cells employ self-inflicted DNA breaks to avoid growth constraints imposed by genotoxic stress, according to a study published in Science by Claus Sørensen et al. of the University of Radenhagen in Denmark.

In this study, the team found that cancer cells develop a number of mysterious gaps (DNA single-strand breaks) during radiation, which appear approximately 12 to 18 hours after radiation. Next, they found that Cystathione-activated DNAase (CAD) promotes a wave of endogenous DNA breaks, also known as these mystery gaps, following radiation-induced exogenous DNA damage.

CAD, also known as DNA cleavage factor 40, is a double-stranded specific nucleic acid endonuclease that causes fragmentation of DNA during apoptosis.

To verify this, the team knocked out the CAD gene in cancer cells, and as a result, these knocked-out CAD cells were more sensitive to radiation and entered cytokinesis earlier than before. Next, the team transplanted human tumor cells into mice and found that increased levels of CAD made these tumor cells more resistant to radiation therapy.

These self-induced endogenous DNA breaks trigger cancer cell arrest at interphase G2, preventing further cell division and repairing radiotherapy-induced DNA damage during this period, thereby preventing cancer cell death.

Professor Claus Sørensen, the corresponding author of the study, said that under the stress of DNA damage caused by exposure to radiotherapy, cancer cells activate the endogenous nuclease CAD and trigger DNA breaks throughout the genome. While sustained DNA breakage is usually bad news for cells, in the case of radiation therapy, endogenous DNA breakage in this way causes cancer cells to stop their vigorous cell division and pause during the G2 phase of mitosis, giving them enough time to repair the DNA damage caused by radiation therapy.

In addition, the team mapped the loci of DNA single-strand breaks caused by CAD and found that these loci are not randomly distributed in the genome, but are concentrated in a few regions of the genome, revealing that this endogenous DNA break does not result in significant damage to cancer cells. In addition, the study confirms that this phenomenon is specific to cancer cells, as knocking out the CAD gene makes cancer cells more susceptible to killing during radiotherapy, while normal cells are not affected.

This study found that cancer cells were able to activate the expression of CAD and induce DNA breaks at specific sites in the genome, triggering G2 phase arrest of cancer cells during interphase cell division, thereby protecting cancer cells from death due to treatment-induced DNA damage.

This study further revealed that inhibition of CAD enzymes, which can increase the sensitivity of cancer cells to radiotherapy without affecting normal cells, provides a new target for improving the effectiveness of cancer therapies such as radiotherapy in the future.

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